Alpha-Agonists have been shown to lower blood pressure by central mechanisms. Alpha-Methyldopa (alpha-MD) decreases blood pressure by reducing sympathetic outflow from the brain. The alpha-methyl group makes the drug and its metabolites methyldopamine (MDA) and methyl-norepinephrine (MNE) resistant to monoamine oxidase (MAO). The MAO-resistant MNE may be a more effective alpha-agonist than MAO-sensitive norepinephrine and may explain why alpha-MD is an antihypertensive agent while L-dopa is not. This research proposal will test whether alpha-MD can lead to a dose related acceleration of production of the alpha-agonist MNE in hypertensive and normotensive rat brain as a possible explanation for its anti-hypertensive activities. L-Dopa will be co-administered with MAO inhibitors to test whether the addition of the MAO inhibitor will permit L-dopa to increase NE turnover and lower blood pressure in a dose dependent way. Alpha-Methyldopa and L-dopa metabolites will be studied in rat hypothalamus, caudate, and brainstem. Animals will receive steady state infusions of drug and blood pressure measured before and after 24-hour drug infusions. Regional brain catecholamine turnover will be studied by addition of deterium-labeled drug and following incorporation of label into metabolites by mass spectrometry. Concentrations of dopamine, norepinephrine, MDA, and MNE will be assayed by high pressure liquid chromatography with electrochemical detection. Clonidine will also be studied by 24-hour infusion with steady-state measurement of blood pressure fall and catecholamine turnover. A second group of studies will examine brain catecholamine response to blood pressure changes induced by vasoconstrictors and vasodilators. Catecholamine turnover will be measured after 24 hours of vasoconstrictor-induced hypertension and vasodilator-induced hypotension. These experiments should clarify the role of central dopaminergic and noradrenergic systems in direct and reflex regulation of blood pressure.